Amelogenesis imperfecta

Gene: AIRE

Green List (high evidence)

Comment on list classification: There are at least 5 patients reported in literature with biallelic variants in AIRE, diagnosed with APS-1 and presenting with marked enamel hypoplasia (onset mostly in childhood / adolescence). Only one APS-1 patient heterozygous for an AIRE variant presented with enamel hypoplasia. In addition, AIRE knock-out mice showed defective enamel formation (PMID: 37993717). Based on the available evidence, this gene should be rated Green for Amelogenesis imperfecta, with MOI set to BIALLELIC, autosomal or pseudoautosomal.

Created: 5 Nov 2025, 12:48 p.m. | Last Modified: 5 Nov 2025, 1:24 p.m.

Panel Version: 4.9

PMID 19393987 Pavlic and Waltimo-Sirén, 2009
Patients with autoimmune polyendocrinopathy–candidiasis–ectodermal dystrophy (APECED), also known as autoimmune polyglandular syndrome type I (APS 1).
Family 1 - female patient A, 9yo, oldest child of three siblings - compound heterozygote with R257X / 653-7_-5delCTC mutations in AIRE. Presented with hypoplastic enamel, hypoparathyroidism (HPT), hypoadrenocorticism, and chronic mucocutaneous candidiasis (CMC). Siblings asymptomatic, not genotyped.
Family 2 - female proband (patient B) with APECED harboured compound het mutations in AIRE: p.Arg257Ter; p.Thr16Met. Unaffected family members were either carriers or WT. Similarly affected brother (patient C), who harboured the same variants in AIRE.
Patient B presented with ectodermal dystrophy and HPT at age 5, and CMC at age 11. Panoramic tomogram at age 11 showed markedly thin and uneven enamel; premolars erupted with discoloured and hypoplastic enamel; she needed prosthetic crowns for her premolars before age 15; moderate to severe tooth sensitivity.

PMID: 27253668 Bruserud et al., 2016
Report of fifty-two patients from 34 Norwegian families with biallelic variants in AIRE (relatedness?). Enamel hypoplasia, hypoparathyroidism, and CMC were the most frequent components. Of 25 patients examined by a dentist, 18 presented with enamel hypoplasia (72%), onset mostly in adolescence.

PMID: 31905445 Suh et al., 2019
10yo female Korean patient; compound het for c.1513delG (p.Ala505ProfsTer16) and c.1360dupC (p.His454ProfsTer50); presented with Primary adrenal insufficiency, Chronic mucocutaneous candidiasis (since 6 months of age), Dental enamel dysplasia, Hyperpigmentation.

PMID: 35521792 Cranston et al., 2022
Patient 15: age 19 at time of report, compound het. variants c.769C>T, p.(Arg257Ter); c.967_979del13, p.(Leu323fs) in AIRE. Presented with hypoparathyroidism, nail dystrophy, enamel hypoplasia, alopecia, tubulointerstitial nephritis.
Patient 19: onset at age 6, homozygous for c.967_979del13, p.(Leu323fs) - Mutation associated with uniparental isodisomy. Phenotype: hypoparathyroidism, enamel hypoplasia, and adrenal insufficiency.
In this cohort, 7% of mutation positive individuals, and 3% of mutation negative probands, presented with enamel hypoplasia. Ethnic background not disclosed.

Functional evidence:
PMID: 37993717 Gruper et al., 2023
Enamel defects similar to APS1 presentation develop in 20-50% of children with coeliac disease. Study shows that both APS1 and coeliac disease patients develop autoantibodies (mostly IgA isotype) against ameloblast specific proteins, leading to defects in enamel formation.
AIRE-deficient (-/-) mice have defective enamel formation; the KO mice showed autoreactivity to ameloblast antigens (slot-blot immunoassay).

Only 1 patient reported with a heterozygous variant in AIRE with enamel hypoplasia:
PMID: 37235056 Oftedal et al., 2023
Family X (II-I) - Female, USA - c.1102C>G, p.Pro368Ala - heterozygous variant, present in 14 individuals in gnomAD v4 (het only); Revel score = 0.27 Benign Supporting. Presented with migraines, chronic constipation, poor appetite, recurrent fever, proteinuria, hypoparathyroidism, enamel hypoplasia; positive for autoantibodies against IL-17A. Seq method: WES.
10 other patients with heterozygous variants in AIRE and APS1 did not present with enamel hypoplasia. Authors highlight incomplete penetrance of the dominant-negative mutations reported.

AIRE is linked to AR & AD Autoimmune polyendocrinopathy syndrome , type I, with or without reversible metaphyseal dysplasia, 240300 (OMIM, accessed 5th Nov 2025).

Created: 5 Nov 2025, 12:34 p.m. | Last Modified: 5 Nov 2025, 1:26 p.m.

Panel Version: 4.9

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Autoimmune polyendocrinopathy syndrome , type I, with or without reversible metaphyseal dysplasia, OMIM:240300; autoimmune polyendocrine syndrome type 1, MONDO:0009411; amelogenesis imperfecta, MONDO:0019507

Publications

• 19393987
• 27253668
• 31905445
• 35521792
• 37993717
• 37235056

Green List (high evidence)

It is well reported that 70-90% of patients with APS-1 (# 240300) have enamel formation defects of various severity. These patients have mutations in the AIRE gene (see PMID 19393987;27253668).

Paper in 2023 (PMID 37993717) reported that there is autoreactivity against enamel antigens in Aire-/- mouse models and that this is also seen in (against ameloblast-specific proteins) in patients with APS-1. The authors looked at 17 patients total and saw autoantibodies in all to enamel specific proteins, see figure 1F.

Immunofluorescence microscopy analysis demonstrated largely overlapping signals from APS-1 serum with that from AMELX- and LAMB3-specific antibodies. Moreover, ELISA analyses revealed that both paediatric and adult patients with APS-1 have IgA autoantibodies against several ameloblast antigens, including LAMB3, FAM20A, ENAM and AMELX, or IgG1 autoantibodies against ACPT. Overall, all patients tested with APS-1 developed autoantibodies against at least one of the five major ameloblast antigens, with distinct reactivity clusters. Furthermore, patients with severe enamel defects had significantly higher levels of autoantibody reactivity against all of the tested enamel antigens compared with those with mild enamel defects or age-matched healthy control individuals. Moreover, canines, which have the longest mineralization period (around 6.5 years), had the most pronounced enamel defects, in comparison to incisors or first molars, of which the mineralization period is significantly shorter (around 4.5 and 3  years, respectively), suggesting that the longer the mineralization period, the higher the chance for enamel-specific autoantibodies to interfere and cause damage in enamel formation.

This is a really interesting mechanism of disease, whereby mutations in AIRE can cause the development of self antigens against the proteins that make enamel, which leads to amelogenesis imperfecta. Note that the paper does not specify whether patients were mono or biallelic carriers of the AIRE variants, note that OMIM records that both mono and balletic variants can cause APS-1.

Note that the authors also looked at patients with coeliac disease and found similar autoantibodies against enamel proteins.
Sources: Literature

Edit: I didn't add Amelogenesis imperfecta to the phenotype list. Can you please add this! I can't seem to add it in retrospect!

Created: 14 Jul 2025, 2:16 p.m. | Last Modified: 14 Jul 2025, 2:18 p.m.

Panel Version: 4.5

Mode of inheritance
BOTH monoallelic and biallelic, autosomal or pseudoautosomal

Phenotypes
Addison disease; hypoparathyroidism; chronic mucocutaneous candidiasis

Publications

• PMID: 37993717
• 19393987
• 27253668